Summary
The effect of systemic inhibition of PAI-1 expression in rats by PS-16R, a phosphorothioate
analogue of hexadecadeoxyribonucleotide complementary to a signal peptide coding sequence
of rat PAI-1 mRNA, on PAI-1 activity in blood plasma and thrombus formation was studied
in rat models for experimental thrombosis. In previous in vitro studies, oligonucleotides of PS-16R family have been shown to inhibit efficiently
PAI-1 synthesis in endothelial cells by antisense mechanism. When PS-16R was administered
intravenously as a single bolus injection (1 to 5 mg per rat), it produced a significant
reduction in PAI-1 activity of blood plasma. This effect was both time- and concentration-dependent.
Under the same conditions, three groups of rats were treated with control oligodeoxynucleotides
such as PS-16R with double mismatches, with scrambled sequence, and an oligodeoxynucleotide
with sense sequence (complementary to PS-16R), respectively. Based on these preliminary
experiments, a low dose of 1.5 mg per rat was selected to produce approximately 20-30%
reduction of PAI-1 activity in blood plasma and the effect of such a decrease in PAI-1
expression was tested on thrombus formation in two rat models for experimentally induced
thrombosis. Such a limited decrease in PAI-1 activity produced a significant antithrombotic
effect in the arterial thrombosis model. There was a profound delay in the occlusion
time in rats treated with PS-16R when compared to control animals (80 ± 3 and 55 ±
3 h, respec tively), although blood plasma activity of PAI-1 in the same groups of
rats differed only by 20%. There was also a tendency to reduce both an incidence of
venous thrombosis (58.33 and 68.11%, respectively) and thrombus weight (2.1 ± 0.4
and 2.9 ± 0.9 mg, respectively) in the animals treated with PS-16R. However, this
effect was not significant. Thus, low dose of PS-16R through inhibition of PAI-1 synthesis
in targeted cells in rats reduced PAI-1 activity in blood plasma and protected against
arterial thrombus formation in the rat.
